14-22519994-C-G

Position:

• chr14-22519994-C-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The ENST00000390513.1(TRAJ24):​c.27C>G​(p.Phe9Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.822 in 760,414 control chromosomes in the GnomAD database, including 259,710 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.85 (55548 hom., cov: 27)
  • Exomes 𝑓: 0.81 (204162 hom.)
• Consequence: TRAJ24 ENST00000390513.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.04

Genes affected

TRAJ24 (HGNC:12053): (T cell receptor alpha joining 24) T cell receptors recognize foreign antigens which have been processed as small peptides and bound to major histocompatibility complex (MHC) molecules at the surface of antigen presenting cells (APC). Each T cell receptor is a dimer consisting of one alpha and one beta chain or one delta and one gamma chain. In a single cell, the T cell receptor loci are rearranged and expressed in the order delta, gamma, beta, and alpha. If both delta and gamma rearrangements produce functional chains, the cell expresses delta and gamma. If not, the cell proceeds to rearrange the beta and alpha loci. This region represents the germline organization of the T cell receptor alpha and delta loci. Both the alpha and delta loci include V (variable), J (joining), and C (constant) segments and the delta locus also includes diversity (D) segments. The delta locus is situated within the alpha locus, between the alpha V and J segments. During T cell development, the delta chain is synthesized by a recombination event at the DNA level joining a D segment with a J segment; a V segment is then joined to the D-J gene. The alpha chain is synthesized by recombination joining a single V segment with a J segment. For both chains, the C segment is later joined by splicing at the RNA level. Recombination of many different V segments with several J segments provides a wide range of antigen recognition. Additional diversity is attained by junctional diversity, resulting from the random additional of nucleotides by terminal deoxynucleotidyltransferase. Five variable segments can be used in either alpha or delta chains and are described by TRAV/DV symbols. Several V and J segments of the alpha locus are known to be incapable of encoding a protein and are considered pseudogenes. [provided by RefSeq, Aug 2016]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.926 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRAJ24	ENST00000390513.1	c.27C>G	p.Phe9Leu	missense_variant	1/1			ENSP00000452134	P1

Frequencies

GnomAD3 genomes AF: 0.851 AC: 129023 AN: 151670 Hom.: 55482 Cov.: 27

Gnomad AFR AF: 0.934

Gnomad AMI AF: 0.964

Gnomad AMR AF: 0.814

Gnomad ASJ AF: 0.849

Gnomad EAS AF: 0.471

Gnomad SAS AF: 0.782

Gnomad FIN AF: 0.781

Gnomad MID AF: 0.820

Gnomad NFE AF: 0.851

Gnomad OTH AF: 0.862

GnomAD4 exome AF: 0.814 AC: 495601 AN: 608626 Hom.: 204162 Cov.: 0 AF XY: 0.814 AC XY: 270710 AN XY: 332446

Gnomad4 AFR exome AF: 0.932

Gnomad4 AMR exome AF: 0.774

Gnomad4 ASJ exome AF: 0.850

Gnomad4 EAS exome AF: 0.517

Gnomad4 SAS exome AF: 0.787

Gnomad4 FIN exome AF: 0.802

Gnomad4 NFE exome AF: 0.847

Gnomad4 OTH exome AF: 0.827

GnomAD4 genome AF: 0.851 AC: 129150 AN: 151788 Hom.: 55548 Cov.: 27 AF XY: 0.843 AC XY: 62516 AN XY: 74164

Gnomad4 AFR AF: 0.934

Gnomad4 AMR AF: 0.814

Gnomad4 ASJ AF: 0.849

Gnomad4 EAS AF: 0.471

Gnomad4 SAS AF: 0.782

Gnomad4 FIN AF: 0.781

Gnomad4 NFE AF: 0.851

Gnomad4 OTH AF: 0.864

Alfa AF: 0.832 Hom.: 5723

Bravo AF: 0.855

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	15

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1483979; hg19: chr14-22988972;